Cellular Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) belongs to the death effector domain superfamily, which is important in regulating apoptosis and proliferation. c-FLIP inhibits the extrinsic recep-tor-mediated apoptotic pathways and intrinsic mitochondrial apoptotic pathways through competition with caspase-8 for recruitment to Fas-associated death domain protein. Moreover, the cleavage products (i.e., p43-FLIP fragment and p22-FLIP fragment) directly acti-vate NF-κΒ, Erk survival signaling, and other non-apoptotic signaling pathways. The c-FLIP (L) can function either as an anti-apoptotic molecule, in a way analogous to c-FLIP (S) and c-FLIP (R), or as a pro-apoptotic molecule to facilitate the activation of caspase-8 at the death-induced signaling complex. The identified dual functionality of c-FLIP depends on various factors, including its expression level, interaction with caspase-8, and its subcellular localization. c-FLIP is frequently over-expressed in many different tumor types, and con-tributes to tumor cell immune surveillance, chemotherapy resistance, and apoptosis-resistance induced by TNFα, TRAIL, and FasL. Fur-thermore, c-FLIP is essential in obtaining aggressive biological behaviors, and is useful in predicting the prognosis of patients with vari-ous malignant tumors. This review focuses on the molecular mechanisms that control the dual regulation of c-FLIP in life/death deci-sion at death-induced signaling complex. Increasing evidence supports the function of c-FLIP as a tumor therapeutic marker to restore an apoptotic response for TRAIL therapy in cancers. Insight into these processes will improve our understanding of apoptosis, and pro-vide new approaches for rational treatment strategies.

Objective To investigate the significance of abnormal gene in histologically normal mammary epithelial tissue for the early diagnosis of breast cancer. Methods Microarray technology was used to identify abnormal gene expres-sion and analyzed bioinformatics of normal mammary epithelial tissue in breast cancer patients and healthy normal control to establish a model for early diagnosis of breast cancer. The differentially expressed genes were screened by using signal path-way enrichment analysis. The accuracy (Ac), sensitivity (Sn) and specificity (Sp) were used to measure the prediction accura-cy of the different methods. Results The best prediction model was derived from the combination of differential genes en-riched from KEGG and BioCarta database. The number of differential expressed genes in three random created prediction models was reduced from 22 to 7, 14 to 3 and 18 to 4. However, the prediction accuracy was consistent with the model estab-lished from all of the differentially expressed genes, and the average accuracy of all models was 96.3%. Conclusion The prediction model can be simplified with the prediction accuracy unchanged, and thus facilitate the model apply to early diag-nosis and prevention of breast cancer.

Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type family, is a broad-spectrum serine proteinase inhibitor. The expression of TFPI-2 is inversely related to increasing degree of malignancy, suggesting a role of TFPI-2 in the mainte-nance of tumor stability and inhibition of the growth of neoplasma. Aberrant methylation of TFPI-2 promoter cytosine-phosphorothio-ate-guanine (CpG) islands has been widely documented to be responsible for diminished expression of TFPI-2 mRNA and protein dur-ing cancer progression. TFPI-2 expression is significantly up-regulated by the ERK1/2 and JNK signaling pathways and modestly in-creased by VEGF, TNF-alpha, and fibroblast growth factor in time-and dose-dependent manners. TFPI-2 can maintain the stability of the tumor environment and inhibit invasiveness and growth of neoplasms. TFPI-2 has also been shown to regulate proliferation, apopto-sis, and vasculogenic mimicry of tumor cells, which may contribute significantly to tumor growth inhibition. Restoration of TFPI-2 ex-pression in tumor tissue inhibits tumor growth and metastasis, which creates a novel possibility of cancer patient treatment. This review focuses on the expression and the molecular regulation mechanisms of TFPI-2 in malignant tumors that control the functions of TFPI-2 in proliferation, apoptosis, and angiogenesis. Insight into these processes will improve our understanding of TFPI-2 and provide new ap-proaches for rational treatment strategies.

Objective To investigate the expression of substance P ( SP) and neurokinin-1 recep-tor (NK1R) in patients with breast cancer and to further understand the correlations of them with the clinico-pathological features and the prognosis of breast cancer.Methods SP levels in serum samples and superna-tants of breast cell culture were measured by ELISA.The expression of total NK1R, full-length NK1R (NK1R-FL) and truncted NK1R (NK1R-Tr) in 82 patients with breast cancer and 30 patients with breast hyperplasia were detected by using immunohistochemistry and Western blot.Results The levels of SP in patients with breast cancer were higher than those in patients with breast hyperplasia and healthy subjects ( P<0.05) .The expression of NK1R-FL was inhibited, while the expression of NK1R-Tr was significantly en-hanced in breast cancer tissues as compared with those in normal and hyperplastic breast tissues (P<0.01). Compared with patients with ductal carcinoma in situ ( DCIS ) , patients with invasive ductal carcinoma (IDC) showed a decreased expression of NK1R-FL, but an increased expression of NK1R-Tr (P<0.05). The stages of breast cancer classified by using the TNM system showed a negative correlation with NK1R-FL expression, but positive correlations with the expression of NK1R-Tr and SP (P<0.01).Moreover, the en-hanced expression of NK1R-Tr and SP and suppressed expression of NK1R-FL were positively related to lymph node metastasis and high expression of vascular endothelial growth factor ( VEGF) , human epidermal growth factor receptor 2 ( HER2) and Ki-67, but negatively related to the expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer tissues (P<0.05).The expression of NK1R-FL and NK1R-Tr showed no significant correlation with age, histological grades and the expression of P53 in breast cancer tissues (P>0.05).Conclusion The invasion and metastasis of breast cancer showed a negative cor-relation with the expression of NK1R-FL, but a positive correlation with the expression of NK1R-Tr and SP.

Objective: This study aimed to examine the number of activated circulating endothelial cells (aCECs) in the peripheral blood of patients with non-small cell lung cancer (NSCLC), and investigate the relationship among aCECs, anti-angiogenic therapy, and prognosis of NSCLC patients. This study also aimed to identify novel predictive markers for anti-angiogenic therapy, and provide basic data and experimental basis for establishing an evaluation system for this therapy. Methods: A total of 142 NSCLC patients were randomly divided into the chemotherapy group (Group 1) and combined therapy group (i.e., chemotherapy plus endostatin, Group 2). The number of aCECs was measured using flow cytometry by detecting the expression status of CD105 and CD146 in the peripheral blood. The correlation between the changes in aCECs and efficacy of drug treatment was statistically analyzed using SPSS software. Results:The number of aCECs in Group 2 increased significantly at 8 and 29 d, two cycles, 50 and 71 d, and four cycles after treatment, respectively (P<0.05). In particular, aCECs amount in cases of progressive disease increased more significantly after combined therapy (P<0.05). A negative correlation was found between the treatment cycle and difference in aCECs amount before and after therapy (r=-0.970, P=0.001). A negative correlation was also observed between the difference in aCECs amount and time to tumor progression (TTP) (r=-0.351, P=0.039). Therefore, the difference in aCECs amount before and after therapy could serve as an important predictor for TTP in NSCLC patients. Conclusion:CD105 and CD146 reflected the activation status of endothelial cells, and responded to the drug treatment. Thus, CD105 and CD146 could act as ideal markers for aCECs. The number of aCECs increased during cancer progression, but significantly decreased after long-term treatment. Therefore, the change in aCECs amount may be a useful marker in predicting the efficacy of anti-angiogenic therapy.

Objective To evaluate a therapeutic strategy using aromatase inhibitors and TAM in postmenopausal Luminal B breast cancer patients. Methods The clinical data of 733 primary breast cancer cases receiving postoperative endocrine thempy from July 2002 to Mar 2005 in Tianjin Cancer Hospital were retrospectively analyzed.Diagnosis was confirmed by pathology in all the cases.All patients were post-menopausal and ER-positive.501 patients were given tamoxifen(TAM 2.5 mg qd,po),232 patients were given aromatase inhibitors(Letrozole 10 mg bid,po).The follow-up time ranged from 36 to 90 months.Median follow-up time was 46 months.Results The disease-free-survival(DFS)rate of Luminal B breast cancer patients in aromatase inhibitors(AIS)group was higherthan that in TAM group(90.6% vs.88.6%,P=0.038).In TAM group,subgroup analysis showed 3-year DFS of node-positive with HER2(+)is lower than that of node-positive with Her-2-negative(88.2% vs.90.4%,P=0.037);3-year DFS of ER+/PR+ group in HER2(+) patients was higher than that of ER+/PR-group(90.8% vs.89.5%.P=0.032).In AIs group,in spite of the axillary lymph node status,there was no significant difference of 3-year DFS between HER2(+)patients and HER2(-)ones(P>0.05).3-year DFS of ER+/PR+with HER2(+) patients was higher than that of ER+/PR-ones with HER2(+)(91.9% vs.90.5%,P=0.029).Hot flush,vaginal bleeding and thromboembolics in AIS group is less frequent,but muscle pain and bone fracture is more common than that in TAM group(P<0.05).Conclusion Compared to TAM, AIs is more effective and safer with postmenopausal Luminal B patients,and the effect is independent on node stams.

OBJECTIVETo investigate the expression of apoptotic regulator c-FLIP(L) in invasive breast carcinoma tissues, and to evaluate its correlation with molecular subtyping and clinical prognosis.

METHODSImmunohistochemistry using EnVision staining for c-FLIP(L) was performed in 264 cases of invasive breast carcinomas and matched adjacent normal breast tissue samples from January 1996 to December 1999. ER, PR, HER2, Ki-67, CK5/6 and EGFR were evaluated by immunohistochemistry in order to classify the tumors into five molecular subtypes and the difference of c-FLIP(L) expression in these molecular subtypes was also analyzed. The influence of c-FLIP(L) expression on prognosis was evaluated by Kaplan-Meier curves and multi-factor Cox proportional risk model.

RESULTSHigh expression of c-FLIP(L) was observed in 84.5% (223/264) of cases of invasive breast carcinomas which were significantly higher than the 45.1% (119/264) of cases in adjacent normal epithelium of breast (χ² = 89.78, P = 0.000). The expression of c-FLIP(L) in luminal B (HER2 positive) and basal-like breast cancers was 78.1% (25/32) and 46.2% (18/39), respectively, with significant difference (P < 0.05). Moreover, the expression of c-FLIP(L) in luminal B (HER2 positive) was higher than in luminal A cancers (P < 0.05), and the expression of c-FLIP(L) in HER2 positive cancers was higher than in basal-like cancers (P < 0.01). C-FLIP(L) showed deep yellow staining in node positive breast cancer with a high-expression rate of 93.1% (134/144); whereas the expression was sporadic and light yellow in node negative breast cancer with a lower high-expressed rate of 72.5% (87/120, P < 0.01). C-FLIP(L) expression had significant influence on disease-free survival time, with c-FLIP(L)-positive patients showing poor prognosis (P < 0.01). Multi-factor Cox proportional risk model analysis showed that expression of c-FLIP(L), lymph nodes status and molecular subtypes were independent prognostic factors for invasive breast carcinomas (P < 0.05).

CONCLUSIONSC-FLIP(L) is highly expressed in invasive breast carcinomas, and its expression level is closely related to the molecular subtypes and clinical prognosis of breast cancer patients. Thus, c-FLIP(L) could be used as an important tumor marker for personalized cancer therapy and prognostic prediction.

Aged ; Biomarkers, Tumor ; metabolism ; Breast ; metabolism ; Breast Neoplasms ; classification ; metabolism ; mortality ; CASP8 and FADD-Like Apoptosis Regulating Protein ; metabolism ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Prognosis ; Receptor, ErbB-2 ; metabolism

Objective:To investigate the safety and short-term efficacy of laparoscopic pro-ximal gastrectomy (LPG) for proximal gastric cancer and adenocarcinoma of esophagogastric junction.Methods:The retrospective cohort study was conducted. The clinicopathological data of 385 patients with proximal gastric cancer and adenocarcinoma of esophagogastric junction who underwent LPG in the 15 medical centers, including the First Affiliated Hospital of Xiamen University et al, from January 2014 to March 2022 were collected. There were 304 males and 81 females, aged (63±9)years. Of the 385 patients, 335 cases undergoing LPG were divided into the laparoscopic group and 50 cases undergoing open proximal gastrectomy were divided into the open group. Observation indicators: (1) intraoperative and postoperative situations; (2) follow-up; (3) stratified analysis. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Wilcoxon rank sum test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Repeated measurement data were analyzed using the repeated ANOVA. Results:(1) Intraoperative and postoperative situations. The operation time, cases with reconstruction of digestive tract as esophagogastric anastomosis and esophageal-jejunal anastomosis, cases with postoperative pathological staging as stage 0?Ⅰ and stage Ⅱ?Ⅲ, duration of postoperative hospital stay, cases with postoperative early complications were (212±96)minutes, 270, 65, 177, 107, 10(range, 8?14)days, 40 in patients of the laparoscopic group, with 51 cases missing the data of postoperative pathological staging. The above indicators were (174±90)minutes, 39, 11, 22, 28, 10(range, 8?18)days, 10 in patients of the open group. There were significant differences in the opera-tion time and postoperative pathological staging between the two groups ( t=2.62, χ2=5.93, P<0.05), and there was no significant difference in the reconstruction of digestive tract, duration of post-operative hospital stay, postoperative early complications between the two groups ( χ2=0.19, Z=0.40, χ2=2.50, P>0.05). (2) Follow-up. Of the 385 patients,202 cases were followed up during the post-operative 12 months, including 187 cases in the laparoscopic group and 15 cases in the open group. Cases with reflux esophagitis, cases with esophageal anastomotic stenosis were 48, 11 in patients of the laparoscopic group, versus 5, 2 in patients of the open group, showing no significant difference in the above indicators between the two groups ( P>0.05). The body mass index (BMI), hemoglobin (Hb), albumin (Alb) at postoperative 6 months and 12 months were (21±3)kg/m 2, (130±15)g/L, (40±4)g/L and (21±3)kg/m 2, (132±14)g/L, (41±4)g/L in patients of the laparoscopic group, versus (21±3)kg/m 2, (121±19)g/L, (37±5)g/L and (21±3)kg/m 2, (125±21)g/L, (43±6)g/L in patients of the open group. There were significant differences in postoperative Hb between the two groups ( Fgroup=5.88, Ftime=5.49, Finteraction=19.95, P<0.05) and there were significant differences in time effect of postopera-tive BMI and Alb between the two groups ( Ftime=9.53, 49.88, P<0.05). (3) Stratified analysis. ① Incidence of postoperative of reflux esophagitis and esophageal anastomotic stenosis in patients with different reconstruction of digestive tract. Of the 202 patients, cases with reconstruction of digestive tract as esophagogastric anastomosis and esophageal-jejunal anastomosis were 168 and 34, respectively. The incidence rates of postoperative of reflux esophagitis were 26.79%(45/168)and 23.53%(8/34)in cases with reconstruction of digestive tract as esophagogastric anastomosis and esophageal-jejunal anastomosis, showing no significant difference between them ( χ2=0.16, P>0.05). Cases undergoing esophageal anastomotic stenosis were 13 in patients with reconstruction of diges-tive tract as esophagogastric anastomosis. ② The BMI, Hb, Alb in patients with different reconstruc-tion of digestive tract. The BMI, Hb, Alb were (24±3)kg/m 2, (135±20)g/L, (41±5)g/L in the 168 patients with reconstruction of digestive tract as esophagogastric anastomosis before the operation, versus (23±3)kg/m 2, (130±19)g/L, (40±4)g/L in the 34 patients with reconstruction of digestive tract as esophageal-jejunal anastomosis before the operation, showing no significant difference between them ( t=1.44, 1.77, 1.33, P>0.05). The BMI, Hb, Alb at postoperative 6 months and 12 months were (21±3)kg/m 2, (128±16)g/L, (39±4)g/L and (21±3)kg/m 2, (131±16)g/L, (41±4)g/L in the 168 patients with reconstruction of digestive tract as esophagogastric anastomosis, versus (20±4)kg/m 2, (133±13)g/L, (43±3)g/L and (21±3)kg/m 2, (135±12)g/L, (44±3)g/L in the 34 patients with reconstruction of digestive tract as esophageal-jejunal anastomosis. There were significant differences in the group effect and time effect of postoperative Alb between patients with different reconstruction of diges-tive tract ( Fgroup=15.82, Ftime=5.43, P<0.05), and there was also a significant difference in the time effect of postoperative BMI between them ( Ftime=4.22 , P<0.05). Conclusion:LPG can be used to the treatment of proximal gastric cancer and adenocarcinoma of esophagogastric junction, with a good safety and short-term efficacy.

Objective:To analyze the expression of mismatch repair (MMR) proteins in colorectal cancers (CRC) and to evaluate the feasibility and potential pitfalls of immunohistochemistry (IHC) analysis for MMR.Methods:The IHC sections for MMR proteins were reviewed in 3 428 cases of resected CRC without neoadjuvant therapy at Tianjin Medical University Cancer Institute and Hospital from July 2014 to October 2018. For the cases with unclear MMR IHC results during the initial review, IHC staining was repeated and microsatellite instability (MSI) analysis was performed. Relationships between the expression of MMR proteins and MSI status as well as the clinicopathological parameters were analyzed.Results:IHC staining for MMR was repeated in 28 (0.8%) cases due to poor quality of original IHC sections. Inconsistent results between the original diagnosis and re-diagnosis were found in 119 (3.5%) cases, mainly resulting from PMS2 and MLH1. Finally, 261 (7.6%) cases of CRC showed mismatch repair deficiency (dMMR), mainly from the deficiency of both MLH1 and PMS2 (43.3%,113/261). In the 14 cases with MSI results, the concordant of MSI and MMR was 13 cases. In the 29 dMMR cases with next generation sequencing (NGS) results, the concordant of MSI-high and dMMR was 93.1%(27/29). The cases with inconsistent results between MSI and MMR showed negative expression of MSH6 or PMS2. Twenty-one CRC showed negative expression of MLH1 and partially positive (or weak positive) expression of PMS2, or negative expression of MSH2 and partially positive (or weak positive) expression of MSH6. Among the 19 cases with MSI results, 16 cases were MSI-high, two cases were MSI-low, and one case was microsatellite stable. Compared with mismatch repair proficiency (pMMR), dMMR was more frequently detected in female patients younger than 50 years old, with family history, at early stage (Ⅰ-Ⅱ) CRC, and in the tumors from right colon,with poor differentiation, or mucinous adenocarcinoma/signet ring cell carcinoma (all P<0.05). Conclusions:At present, IHC staining is a clinically effective and convenient method to detect MMR expression, but the operating process and result assessment remain variable and need to be standardized. MSI analysis can be performed in the difficult-to-evaluate cases for MMR to enhance prognostic evaluation and treatment option.

Objective:To investigate the incidence of postoperative complications in Chinese patients with gastric or colorectal cancer, and to evaluate the risk factors for postoperative complications.Methods:This was a national, multicenter, prospective, registry-based, cohort study of data obtained from the database of the Prevalence of Abdominal Complications After Gastro- enterological Surgery (PACAGE) study sponsored by the China Gastrointestinal Cancer Surgical Union. The PACAGE database prospectively collected general demographic characteristics, protocols for perioperative treatment, and variables associated with postoperative complications in patients treated for gastric or colorectal cancer in 20 medical centers from December 2018 to December 2020. The patients were grouped according to the presence or absence of postoperative complications. Postoperative complications were categorized and graded in accordance with the expert consensus on postoperative complications in gastrointestinal oncology surgery and Clavien-Dindo grading criteria. The incidence of postoperative complications of different grades are presented as bar charts. Independent risk factors for occurrence of postoperative complications were identified by multifactorial unconditional logistic regression.Results:The study cohort comprised 3926 patients with gastric or colorectal cancer, 657 (16.7%) of whom had a total of 876 postoperative complications. Serious complications (Grade III and above) occurred in 4.0% of patients (156/3926). The rate of Grade V complications was 0.2% (7/3926). The cohort included 2271 patients with gastric cancer with a postoperative complication rate of 18.1% (412/2271) and serious complication rate of 4.7% (106/2271); and 1655 with colorectal cancer, with a postoperative complication rate of 14.8% (245/1655) and serious complication rate of 3.0% (50/1655). The incidences of anastomotic leakage in patients with gastric and colorectal cancer were 3.3% (74/2271) and 3.4% (56/1655), respectively. Abdominal infection was the most frequently occurring complication, accounting for 28.7% (164/572) and 39.5% (120/304) of postoperative complications in patients with gastric and colorectal cancer, respectively. The most frequently occurring grade of postoperative complication was Grade II, accounting for 65.4% (374/572) and 56.6% (172/304) of complications in patients with gastric and colorectal cancers, respectively. Multifactorial analysis identified (1) the following independent risk factors for postoperative complications in patients in the gastric cancer group: preoperative comorbidities (OR=2.54, 95%CI: 1.51-4.28, P<0.001), neoadjuvant therapy (OR=1.42, 95%CI:1.06-1.89, P=0.020), high American Society of Anesthesiologists (ASA) scores (ASA score 2 points:OR=1.60, 95% CI: 1.23-2.07, P<0.001, ASA score ≥3 points:OR=0.43, 95% CI: 0.25-0.73, P=0.002), operative time >180 minutes (OR=1.81, 95% CI: 1.42-2.31, P<0.001), intraoperative bleeding >50 mL (OR=1.29,95%CI: 1.01-1.63, P=0.038), and distal gastrectomy compared with total gastrectomy (OR=0.65,95%CI: 0.51-0.83, P<0.001); and (2) the following independent risk factors for postoperative complications in patients in the colorectal cancer group: female (OR=0.60, 95%CI: 0.44-0.80, P<0.001), preoperative comorbidities (OR=2.73, 95%CI: 1.25-5.99, P=0.030), neoadjuvant therapy (OR=1.83, 95%CI:1.23-2.72, P=0.008), laparoscopic surgery (OR=0.47, 95%CI: 0.30-0.72, P=0.022), and abdominoperineal resection compared with low anterior resection (OR=2.74, 95%CI: 1.71-4.41, P<0.001). Conclusion:Postoperative complications associated with various types of infection were the most frequent complications in patients with gastric or colorectal cancer. Although the risk factors for postoperative complications differed between patients with gastric cancer and those with colorectal cancer, the presence of preoperative comorbidities, administration of neoadjuvant therapy, and extent of surgical resection, were the commonest factors associated with postoperative complications in patients of both categories.